Lifestyle Factors, Genetic Predisposition, and Dementia risk: A Long-Term Prospective Cohort Study

Post by Sarah Hill

What's the science?

Many diseases are believed to culminate from highly complex interactions between genes and environment. Dementia is no exception in this regard, though the degree to which genetics and lifestyle each contribute to the onset of the disease is currently an active area of research. Previous studies have examined the interplay between genes, health, and lifestyle in dementia, though most have concentrated on a single modifiable health factor (e.g. smoking, diet, etc.). There is a great need for research assessing the effects of multiple genetic and environmental risk factors simultaneously. This week in Nature Medicine, Licher and colleagues demonstrate that multiple modifiable factors associated with a healthy lifestyle are linked to reduced long-term risk of dementia in individuals with a low and intermediate genetic predisposition to the disease.      

How did they do it?

The authors acquired data from a large-scale prospective cohort study (the Rotterdam Study) containing demographic, health, lifestyle, and genetic information for 6,352 participants 55 years of age and older. Using genetic information in the dataset, they assessed the genetic risk of dementia for each subject based on which version (or allele) of the apolipoprotein E (ApoE) gene they carried and whether any additional known dementia-associated genetic mutations were expressed, stratifying individuals into groups of low, intermediate, and high genetic risk. They then assigned a modifiable risk score to each individual based on health and lifestyle and grouped participants into favourable, intermediate, and unfavourable profile groups. The modifiable risk score encompassed six health and lifestyle factors, including smoking status, depression status, diabetes status, physical activity level, level of social isolation, and diet. They also calculated an alternative modifiable risk score based on cardiovascular health to compare with the lifestyle-derived score. The risk of dementia was then computed for each group separately using a Cox proportional hazards model and competing risk models, statistical methods for relating the probability of dementia onset over time to numerous risk factors.    

What did they find?

As expected, dementia risk was higher in participants with a high genetic predisposition to the disease, as well as in individuals with unfavourable lifestyle profiles. Intriguingly, a favourable health and lifestyle profile was associated with reduced long-term risk of dementia in individuals with low to intermediate genetic predisposition to the disease, compared to those with unfavourable profiles. However, the same was not true for those at high genetic risk of dementia, such that no differences in dementia risk were detected in favourable, intermediate, and unfavourable lifestyle groups of highly predisposed individuals. Similar observations were made when the modified risk score was calculated from cardiovascular health. Taken together, these findings suggest that modifiable health and lifestyle factors are promising treatment interventions for those with low and intermediate genetic predisposition to dementia, but are likely ineffective at mitigating dementia risk in highly predisposed individuals.                                            

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What's the impact?

This is one of the first and largest studies to examine the interplay between genes and multiple lifestyle factors simultaneously. These findings are important in contributing to our understanding of dementia risk, as the progression of dementia is thought to be a complex and multivariable process. Findings from this study are particularly valuable for guiding the design of future clinical trials for dementia.    


Licher et al. Genetic predisposition, modifiable-risk-factor profile and long-term dementia risk in the general population. Nature Medicine (2019). Access the original scientific publication here.